This invention relates to therapeutic formulations comprising antibodies specific for the monomeric (unacylated) form of A-protein, and the use of such formulations for the treatment of cancers in a mammal.
A-protein is a cellular enzyme that was first isolated from vertebrate rod photoreceptor cells by Schmidt et al., Invest. Ophthalmol. Vis. Sci., 24:244 (1983). A-protein is also known in the scientific literature by the names Gp, Cockcroft, Trends Biochem. Sci., 12:75-78 (1987); recoverin Dizhoor et al., J. Biol. Chem., 267:1603316036 (1992); and CAR protein, Thirkill et al., Arch. Ophthalmol., 111:974-978 (1993). A-protein has been characterized as a GTP-binding protein (g-protein), Schmidt et al., Invest. Ophthalmol. Vis. Sci., 28:94 (1987), that regulates phosphinositide metabolism by activating phospholipase C, Schmidt et al., Invest Ophthalmol. Vis. Sci., 29:123 (1988).
A-protein exists in two forms; Schmidt et al., Invest. Ophthalmol. Vis. Sci., 30:172 (1989); and Dizhoor et al., J. Biol. Chem., 267:16033-16036 (1992): as an unmodified monomer of approximately 23,000 daltons which is soluble in the cytosol (hereinafter “As”), and as a co-synthetically post-translationally modified form to which a fatty acid is attached by the action of the enzyme N-myristoyl transferase (NMT; E.C.2.3.1.97) (hereinafter “Am”). The modified form of A-protein tends to self-associate as stable pentameric homopolymers with an approximate molecular weight of 130,000 daltons. These homopolymers are peripherally bound to the inner aspect of the cell membrane. The post-translational modification of A-protein induces a conformational change in the protein that renders certain peptides of the protein inaccessible to antibody binding.
In its peripherally membrane-bound form, A-protein is activated by a growth-factor receptor imbedded in the plasmalemma subsequent to activation of the receptor by a growth factor. The persistent activation of this metabolic cascade mechanism results in a sustained release of calcium into the cytosol which ultimately stimulates the cell to divide. This general scheme is referred to as signal transduction (see U.S. Pat. No. 5,100,661).
In non-ocular tissues, A-protein transduces growth signals and is expressed in mitotically active cells including malignant tissues. In cancer, A-protein is over-expressed inside affected malignant cells and into the blood stream. Fragments of the protein are also displayed on the surface of malignant cells. See Thirkill et al., Invest. Ophthalmol. Vis. Sci., 33:2768-2772 (1992).
It is well known that the immune system is a very specific mechanism for the excision of neoplastic tissues. Abbas et al., Cellular and Molecular Immunology, pp. 335-352 (1991). However, the lack of immunogenicity of carcinomas, and particularly tumor cells, has presented a stumbling block to the successful reactivation of the antitumor mechanisms of the immune system.
U.S. Patent Publication No. 20070053893, published Mar. 8, 2007, to Schmidt, discloses a method for reducing immunological tolerance to malignancy using formulations of myristoylCoA and N-myristoyl transferase to treat carcinomas displaying A-protein.
It will be readily appreciated that there exists a need for new and improved methods for treating cancers by blocking the monomeric form of the A-protein, and thereby stimulating the immune system to recognize cancer cells as antigenic targets for T-cells, resulting in a regression of the cancer.